Chunlin Tao

Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel.

ABI-007, an albumin-bound, 130-nm particle form of paclitaxel, was developed to avoid Cremophor/ethanol-associated toxicities in Cremophor-based paclitaxel (Taxol) and to exploit albumin receptor-mediated endothelial transport. We studied the antitumor activity, intratumoral paclitaxel accumulation, and endothelial transport for ABI-007 and Cremophor-based paclitaxel. Antitumor activity and mortality were assessed in nude mice bearing human tumor xenografts [lung (H522), breast (MX-1), ovarian (SK-OV-3), prostate (PC-3), and colon (HT29)] treated with ABI-007 or Cremophor-based paclitaxel. Intratumoral paclitaxel concentrations (MX-1-tumored mice) were compared for radiolabeled ABI-007 and Cremophor-based paclitaxel. In vitro endothelial transcytosis and Cremophor inhibition of paclitaxel binding to cells and albumin was compared for ABI-007 and Cremophor-based paclitaxel. Both ABI-007 and Cremophor-based paclitaxel caused tumor regression and prolonged survival; the order of sensitivity was lung > breast congruent with ovary > prostate > colon. The LD(50) and maximum tolerated dose for ABI-007 and Cremophor-based paclitaxel were 47 and 30 mg/kg/d and 30 and 13.4 mg/kg/d, respectively. At equitoxic dose, the ABI-007-treated groups showed more complete regressions, longer time to recurrence, longer doubling time, and prolonged survival. At equal dose, tumor paclitaxel area under the curve was 33% higher for ABI-007 versus Cremophor-based paclitaxel, indicating more effective intratumoral accumulation of ABI-007. Endothelial binding and transcytosis of paclitaxel were markedly higher for ABI-007 versus Cremophor-based paclitaxel, and this difference was abrogated by a known inhibitor of endothelial gp60 receptor/caveolar transport. In addition, Cremophor was found to inhibit binding of paclitaxel to endothelial cells and albumin. Enhanced endothelial cell binding and transcytosis for ABI-007 and inhibition by Cremophor in Cremophor-based paclitaxel may account in part for the greater efficacy and intratumor delivery of ABI-007.

Abstract 4420: ABI-013: A novel nanoparticle albumin-bound (nab) docetaxel analog with superior antitumor activity over docetaxel

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: Docetaxel-based chemotherapy is currently used to treat patients with a variety of tumors. A critical challenge has been to improve its chemotherapeutic levels without systemic toxicity. We developed ABI-013, a novel analog of docetaxel (Taxotere®) as a solvent (polysorbate 80/ethanol)-free, nanoparticle albumin-bound 70-nm (nab) form with improved stability in vivo as a tumor-targeting chemotherapeutic agent. In this study, we evaluated the comparative antitumor activity of ABI-013 versus Taxotere® in human tumor xenografts. Methods: Subcutaneous human breast (MDA-MB-231), colon (HT29 and HCT-116), and lung (H358) tumors were grown in athymic nude mice and treated intravenously (IV) with ABI-013 (15, 30, 60, 90, 120 or 150 mg/kg) or Taxotere (MTD of 15 mg/kg) on a q4dx3 schedule. Evaluations of anti-tumor activity were based on the number of partial and complete regressions, the median number of days for tumors in each group to reach one tumor mass doubling (T-C) or the percentage tumor growth inhibition (%TGI). Results: Significant dose-dependent TGI was observed with complete or partial tumor regressions in all xenograft models treated with ABI-013. In the MDA-MB-231 breast tumor model, ABI-013 effectively delayed the tumor growth with T-C values of 83.1, 80.7, and >84.8 days at dosages of 120, 90, and 60 mg/kg, respectively, with >96% TGI compared to vehicle control (P < 0.0001 vs. saline). In contrast, Taxotere delayed the tumor growth with a T-C value of 49.5 days and decreased tumor growth by 88% (P < 0.0001 vs. saline). In the HT 29 colon tumor model, Taxotere revealed dose-limiting toxicity with a 27% body weight loss (BWL) despite 86 to 91% TGI (P < 0.01 vs. saline). In contrast, ABI-013 (90 mg/kg) caused complete tumor regression with a maximum BWL of 19% (P < 0.0001 vs. saline). Treatment with Taxotere delayed the growth of HCT-116 colon tumor with a T-C value of 14.9 days with a maximum BWL of 21%. In contrast, complete tumor regression was achieved in 40% of ABI-013-treated mice. In the H358 human non-small cell lung cancer model, unlike Taxotere, ABI-013 (60 mg/kg) caused partial tumor regression with minimal toxicity. Conclusion: ABI-013, a solvent-free nanoparticle albumin-bound 70-nm particle form of a novel docetaxel analog, had superior antitumor activity in human breast, colorectal, and lung cancer xenograft models compared with equitoxic doses of solvent-based formulation of docetaxel. The nab form of the novel docetaxel analog shows promise in cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4420.

Abstract 2617: Cardiovascular and CNS safety profile of ABI-013, a novel nanoparticle albumin-bound (nab) analog of docetaxel

Background: ABI-013 is an albumin-bound 70-nm nanoparticle form of a novel docetaxel analog with improved activity in vivo as a tumor-targeting chemotherapeutic agent. Because docetaxel-induced microtubule stabilization has the potential to cause contractile dysfunction in cardiac hypertrophy, the effects of ABI-013 on the cardiovascular (CV), respiratory, and central nervous system (CNS) were examined. Methods: In the cardiopulmonary safety study, male conscious telemetered cynomolgus monkeys (n = 4/group) were administered ABI-013 intravenously (IV) over 30 min at 0, 2, 5 and 10 mg/kg weekly for 4 weeks following a 4×4 Latin Square dosage regimen. Parameters recorded by telemetry included arterial blood pressure, heart rate, respiratory rate, intra-abdominal body temperature, electrocardiogram (ECG, lead II: PR, QRS, RR, QT, and QTcB), and motor activity for up to 24 h postdose. Blood cardiac Troponin I and creatine kinase (CK) isoenzyme levels and arterial blood gas parameters (pH, pO2, pCO2, O2Hb, sO2, HCO3) were also evaluated. In the CNS safety study, male and female Sprague-Dawley rats (n = 4 animals/sex/group) were given single IV doses of ABI-013 (3.5 or 5 mg/kg) or docetaxel (Taxotere®, 3.5 mg/kg). Functional observation battery, locomotor activity, and motor coordination were evaluated for 5 days to assess changes in behavioral parameters. In addition, ABI-013 and Taxotere® were evaluated in an in vitro human ether-a-go-go (HERG) potassium channel patch-clamp assay using hERG-transfected HEK293 cells. Results: In the cardiopulmonary safety studies in monkeys, there were no statistically significant difference in ECG data (PR, QRS, RR, QT, and QTcB), arterial BP (systolic, diastolic, and mAP), respiratory rate, intra-abdominal body temperature, motor activity, and arterial blood gas parameters (pH, pO2, pCO2, O2Hb, sO2, HCO3) between the ABI-013 dose groups and the control group. The levels of cardiac Troponin I and cardiac-specific CK-MB levels remained within normal limits. In the CNS safety study, ABI-013 had no adverse effects on motor activity, behavioral changes, coordination, and sensory/motor reflex responses in the conscious rat at both dose levels. In the whole cell patch-clamp assay, the inhibitory effect of ABI-013 on hERG currents was 70-fold less potent than that of docetaxel. Conclusions: ABI-013 infusion once weekly for 4 wks was well-tolerated at all dose levels. All ECG and pulmonary evaluations were normal with no indication of conduction abnormalities or cardiac muscle toxicity with a no-observed-adverse-effect level (NOAEL) determined at 10 mg/kg. The results of these preclinical studies in monkeys and rats provide evidence that ABI-013 is a safe antitumor agent without cardiovascular or CNS effects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2617.